Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are a group of fatal, transmittable neurodegenerative diseases. Specific examples of TSE include scrapie, which affects sheep and goats, bovine spongiform encephalopathy (BSE), transmissible mink encephalopathy, feline spongiform encephalopathy and chronic wasting disease (CWD). In humans, TSE diseases may present themselves as kuru, Creutzfeldt-Jekob disease (CJD), Gerstmann-Straussler-Scheinker Syndrome (GSS), fatal insomnia and variant Creutzfeldt-Jekob disease (vCJD). vCJD emerged in humans as a result of the BSE epidemic in Britain and is most probably caused by the consumption of food products derived from cattle infected with BSE or “mad cow disease.” (Will et al. (1996) Lancet 347:921-925) Because the incubation period for the orally contracted disease may be more than 20 years in human, the true incidence of vCJD may not become apparent for many years.
In addition to ingestion of infected products of bovine origin, blood transfusion and organ transplantation represent another mode of transmission of vCJD among humans (Brown et al. (1998) Transfusion 38:810-816; Diringer et al. (1984) Archives of Virology 82:105-109; Manuelidis et al. (1978) Nature 271:778-779). Major concerns were raised since the mid-1990s that vCJD can be transmitted through blood transfusion or other blood products from TSE-infected individuals. These individuals may be asymptomatic during the long pre-clinical and incubation phase of vCJD, and blood obtained from such donors may be able to transmit the disease to persons receiving the blood or blood products derived from the donor.
There are so far at least four reported human cases of blood transfusion acquired vCJD in the United Kingdom. Of 64 people who received whole blood from 22 donors, 4 people went on to develop vCJD. In the first incidence, the recipient became ill 7 years after receiving red cells from the donor who remained asymptomatic and only showed signs of vCJD until 3 years after the donation (Llewely et al. (2004) Lancet 363:417-421). In the second incidence, the donor died of vCJD two years after donation, and the recipient died of an aneurysm (not vCJD) 5 years after donation (Peden et al. (2004) Lancet 364:527-529). On autopsy of the recipient, PrPsc was present in lymph node and spleen, but not the brain. In the third incidence, the recipient died of vCJD seven and half years after transfusion from a donor who developed vCJD 20 months after the donation (Wroe et al. (2006) Lancet 368:2061-2067). The fourth incident occurred in a recipient eight and half years after a transfusion from the same donor in the third case (Health Protection Agency—Health Protection Report, (2007) Vol 1, No 3, 26. Available at: http://www.hpa.org.uk/hpr/archives/2007/news2007/news0307.htm).
A common feature of all prion diseases is the conversion of the normal cellular prion protein (PrPc) into an abnormal isoform (PrPsc). The difference between PrPc and PrPsc are believed to be purely conformational, with PrPc having primarily alpha-helical structures and PrPsc having primarily beta sheets that frequently assemble to form aggregates. PrPsc acts as a template to induce normal protein molecules to convert into the same abnormal isoform, which then in turn covert more PrPc into PrPsc (Prusiner et al. (1998) Proc. Natl. Acad. Sci. USA 95:13363-13383). This autocatalytic process leads to exponential formation of neurotoxic PrPsc aggregates (Aguzzi et al. (2007) Nat Rev Mol. Cell Biol. 8:552-561). Prion protein ligands and uses thereof have been described in WO04/050851, WO06/010915, WO04/090102, and WO06/044459.
Studies have shown that the earliest appearance of prion infectivity in the blood may occur during the early stage of the incubation period of the disease (Brown et al. (2006) Blood infectivity in the transmissible spongiform encephalopathies. Chapter 4 In: Turner M L, ed. 95-118). Because it can be a long time before the onset of disease symptoms, silently infected individuals may still be considered as healthy active blood donors. Furthermore, some individuals may be permanently or transiently infected without developing the disease. It is thus difficult if not impossible to ensure that sources of blood for blood derived products are prion free.
Albumin-based nanoparticle compositions have been developed as a drug delivery system for delivering substantially water insoluble drugs. See, for example, U.S. Pat. Nos. 5,916,596; 6,506,405; 6,749,868, and 6,537,579 and also in U.S. Pat. Pub. Nos. 2005/0004002 and 2007/0082838. The albumin-based nanoparticle technology utilizes the unique natural properties of the protein albumin to transport and deliver substantially water insoluble drugs to the site of disease. These nanoparticles are readily incorporated into the body's own transport processes and are able to exploit the tumors' attraction to albumin, enabling the delivery of higher concentrations of the active drug to the target site. In addition, the albumin-based nanoparticle technology offers the ability to improve a drug's solubility by avoiding the need for toxic chemicals, such as solvents, in the administration process, thus potentially improving safety through the elimination of solvent-related side effects.
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